This is an application in response to a program announcement for studies to examine racial/ethnic differences in the etiology of type 2 diabetes. The PI proposed a cross-sectional design to examine the time course of change in insulin and insulin resistance that lead to diabetes. The proposed project will: 1) characterize insulin sensitivity, secretion and clearance in African-Americans (AA) and Caucasian-Americans, and 2) determine whether depressed insulin sensitivity (greater insulin resistance) or hyperinsulinemia is likely to be the primary defect. All information regarding differences in insulin sensitivity, secretion and clearance will be obtained from a single frequently sampled intravenous tolerance test and subsequent minimal modeling. A stable isotope of glucose will be used to differentiate glucose uptake from glucose production. Measurement of C-peptide will be performed to differentiate insulin secretion from insulin clearance. Both obese and non-obese AA and C individuals will be studied to examine obesity-ethnic interactions. Free fatty acid concentrations will be measured throughout the glucose tolerance test to begin to address the potential physiological ramifications of chronic hyperinsulinemia among AA subject. The PI believes that the primary defect in conferring lower insulin sensitivity in AA vs C subjects is a defect in hepatic insulin extraction (clearance). The chronic hyperinsulinemia that results from this defect will ultimately result in peripheral (skeletal muscle) insulin resistance.